Anomeric stereoauxiliary strategy enables efficient synthesis of wide-ranging imidazo[1,5-α]pyridines

Abstract

Imidazo[1,5-α]pyridines are one of the most important groups of N-heterocyclic compounds, with wide applications in pharmaceutics, chemical science and material science. Despite tremendous progress in their synthesis over the past decade, a number of important imidazo[1,5-α]pyridines as intermediate products remain inaccessible, such as 1-alkylimidazo[1,5-α]pyridines. Herein, we report a novel anomeric stereoauxiliary approach for the preparation of this important class of compounds. It strongly expands the scope of readily accessible imidazo[1,5-α]pyridines well beyond the existing state-of-the-art methods. More than 80 products with a substantial number of deemed unattainable ones were synthesized. With the first time accessibility to alkyl(pyridine-2-yl)methanone substrates, a group of important deuterated imidazo[1,5-α]pyridines derivatives were also efficiently achieved. The mechanism containing a key seven-membered ring transition state via α-anomeric stereoauxiliary for this new synthetic pathway is provided in great detail and supported by electronic structure calculations. In total, this novel synthetic approach for a broad range of imidazo[1,5-α]pyridines involving the native stereochemistry will open a new window for research endeavors in diverse fields, encompassing organic synthesis, biomass conversion via cleavage of C-N bonds and medicinal chemistry.